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Riboflavin deficiency in infants and children with heart disease
Riboflavin deficiency in infants and children with heart disease Moshe Steier, M.D. Rafael Lopez, M.D. Jack M. Cooperman, Ph.D. New York, N. Y.
It has been shown t h a t folic acid deficiency m a y be a complication of h e a r t disease in adults ~-:~and in infants and children2 Among the m e c h a n i s m s advanced to explain this deficiency were gastrointestinal malabsorption 5 and excessive u r i n a r y excretion. ~ However, these mechanisms m a y also result in other vitamin deficiencies. I n order to determine whether the l a t t e r do occur, we investigated in infants and children with congenital and acquired h e a r t disease, a deficiency of riboflavin, a m e m b e r of the B complex of vitamins.
Subjects and methods T h i r t y one children ranging in age from 1 m o n t h to 18 years were the s t u d y subjects. Twenty-seven had congenital cardiac defects and f o u r had rheumatic h e a r t disease. C o n v e n t i o n a l x-rays and 13 lead electrocardiograms were done on all patients. T h e 27 with congenital h e a r t disease u n d e r w e n t cardiac c a t h e t e r i z a t i o n and angiography. E r y t h r o c y t e s e d i m e n t a t i o n rate, Creactive protein, antistreptolysin O titer, serum complement, e n z y m e studies, stool analyses, and various cultures were done where necessary to make the diagnosis. T h e lesion in each case is described in Tables I and II. T h e heights and weights of each child were recorded and plotted on the percentile c h a r t developed by Dr. H a r o l d C. S t u a r t for comparison of these children with the general population. 4 Riboflavin deficiency was d e t e r m i n e d from the From the Department of Pediatrics, New York Medical College, Flower and Fifth Avenue Hospitals, and Metropolitan Hospital Center, New York, N. Y. Received for publication May 27, 1975. Reprint requests: Dr. Jack M. Cooperman, Department of Pediatrics, New York Medical College, 1249 Fifth Ave., New York, N. Y. 10029.
August, 1976, Vol. 92, No. 2, pp. 139-143
estimation of the degree of s a t u r a t i o n of e r y t h r o cyte glutathione reductase ( E G R ) with flavin adenine dinucleotide (FAD), by a modification of the m e t h o d of Glatzle and associates. 7 Details of this m e t h o d were previously reported. 8 T h e results are expressed as the activity coefficient (AC) which is a measure of the i n c r e m e n t of E G R activity when exogenous F A D is added to the reaction mixture. N o r m a l values range from 0.9 to 1.2. Values above 1.2 indicate deficiency i n infants and children. The prevalence of riboflavin deficiency in the children with h e a r t disease was c o m p a r e d to t h a t in a group of 100 n o r m a l infants and children of the same socioeconomic level who were free of acute or chronic infection, diarrhea, or vomiting.
Results Eleven of the 31 children with cardiac disease had biochemical evidence of riboflavin deficiency with AC values ranging from 1.29 to 1.71 (Table I). This was a significantly higher prevalence t h a n t h a t in a group of normal children of the same socioeconomic status (p < 0.005). In the l a t t e r group 11 of 100 had biochemical evidence of riboflavin deficiency. In each case, the elevated AC values could be returned to within n o r m a l limits in 5 to 8 days, when the riboflavin-deficient children were given 2.4 mg of riboflavin per day orally. Cardiac disease in study subjects. Eight of the 11 children with evidence of riboflavin deficiency had congenital h e a r t disease, four with ventricular septal defect, one with ventricular septal defect with aortic insufficiency, two with tetralogy of Fallot, and one with tricuspid atresia. T h r e e had r h e u m a t i c heart disease with mitral
American Heart Journal
139
Steier, Lopez, and Cooperman
Table I. R i b o f l a v i n - d e f i c i e n t
patients
Percentile Case No.
Age (yr.)
15
1/2
6
1
12
1
19
21~
2
3
4
3
8
5
31
10
25
12
1
13
7
13
Wt.
Ht.
Heart size (ECG, x-ray)
Second diagnosis
EGRA C*
Diagnosis
CHF
Congenital heart disease; ventricnlar septal defect Congenital heart disease; ventricular septal defect Congenital heart disease; tricuspid atresia Congenital heart disease; tetralogy of Fallot Congenital heart disease; tetralogy of Fallot Congenital heart disease; yentricular septal defect Congenital heart disease; yentricular septal defect Rheumatic heart disease; mitral insuffic. + myocarditis Congenital heart disease; ventricular septal defect; aortic insuffic. Rheumatic heart disease; m i t r a l insuffic. + myocarditis Rheumatic heart disease; mitral insuffic. + myocarditis
+
10
25
Left ventricular Pneumonia hypertrophy; large
Penicillin, digoxin, chlorothiazide
11.3
1.6
+
> 10
25
Left ventricular Pneumonia hypertrophy; large
Penicillin, digoxin
10.8
1.5
0
3
3
-
17.8
1.71
0
10
25
-
16.8
1.3
0
> 3
> 10
-
17.3
1.5
+
> 3
3
Left ventricular hypertrophy; normal Right ventricular hypertrophy; normal Right ventricular hypertrophy; normal Biventricular Pneumonia hypertrophy; large
Penicillin, digoxin
11.5
1.57
+
> 50
> 25
Penicillin, digoxin, chlorothiazide
9.8
1.43
+
75
50
Left ventricular hypertrophy; large
-
-
14.2
1.5
0
25
50
Normal; normal
-
-
12.5
1.3
+
> 50
> 25
Left ventricular hypertrophy; large
-
Penicillin, prednisone, digoxin
13.0
1.29
+
50
75
Left ventricular hypertrophy; large
Penicillin, prednisone, digoxin, KC1
12.0
1.38
Biventricular hypertrophy; large
Pneumonia
Asthma
Drugs
Hb (Gm./ dl.)
*EGRAC: erythrocyte glutathione reductase activity coefficient.
insufficiency and myocarditis. S e v e n o f t h e 11 were in congestive heart failure (CHF) when these studies were performed. O f t h e 20 w i t h n o e v i d e n c e o f r i b o f l a v i n d e f t c i e n c y , 19 h a d c o n g e n i t a l d i s e a s e a n d o n e h a d rheumatic heart disease. Only four were in congestive heart failure (Table II).
Socioeconomic factors. A l l the infants and 140
children in this study were from the same socioeconomic level and no gross dietary differences could be discerned between the groups. S e v e n o f t h e 11 r i b o f l a v i n - d e f i c i e n t p a t i e n t s were below the fiftieth percentile for weight and eight were below the fiftieth percentile for height. I n c o m p a r i s o n , 10 o f t h e 20 w i t h o u t r i b o f l a v i n deficiency were below the fiftieth percentile for
August, 1976, Vol. 92, No. 2
Riboflavin deficiency in heart disease
Table II. Non-riboflavin-deficient patients Percentile Case No. 21
22
16
3
14
17
23
10
30
18
13
11
9
Age
Diagnosis
1 mo. Congenital heart disease; transposition of great vessels 2 mo. Congenital heart disease; tricuspid atresia 2 too. Congenital heart disease; tricuspid atresia 1 yr. Congenital heart disease; tricuspid atresia 1 yr. Congenital heart disease; tetralogy of Fallot 1 yr. Congenital heart disease, ventricular septal defect; persistent ductus arteriosus 1 yr. Congenital heart disease; ventricular septal defect 2 yr. Congenital heart disease; ventricular septal defect; atrial septal defect 2 yr. Congenital heart disease; patent ductus arteriosus 21/2 yr: Congenital heart disease; tetralogy of Fallot 2V2 yr. Congenital heart disease; ventricular septal defect; aortic insuffic. 21/2 yr. Congenital heart disease; ventricular septal defect; atrial septal defect; pulmonary valvular stenosis 3 yr. Congenital heart disease; tetralogy of Fallot
Ht.
Heart size (ECG, x-ray)
Second diagnosis
Hb (Gm./
EG-
Drugs
dl.)
RA C*
Digoxin, penicillin
14.8
1.0
15.3
1.0
16.4
1.0
16.5
1.0
15.4
1.0
12.4
1.0
12.0
1.0
CHF
Wt.
0
< 10
90
Right ventricular hypertrophy; large
0
25
25
0
3
10
0
> 10
> 25
0
3
10
+
50
25
Left ventricular hypertrophy; normal Left ventricular hypertrophy; normal Left ventricular hypertrophy; normal Left ventricular hypertrophy; normal Left ventricular hypertrophy; large
+
3
10
Biventricular hypertrophy; large
+
10
25
Right ventricular hypertrophy; normal
12.2
0.9
0
50
25
Upper limits of normal: normal
13.6
1.0
0
3
25
17.4
1.0
0
10
25
Right ventricular hypertrophy; normal Left ventricular hypertrophy; normal
12.4
1.0
0
3
25
Right ventricular hypertrophy; normal
14.0
0.9
0
25
25
Right ventricular hypertrophy; normal
17.2
1.0
-
-
Digoxin
*EGRAC: erythrocyte glutathione reductase activity coefficient. tPostoperative.
American Heart J o u r n a l
141
Steier, Lopez, and Cooperman
Table II. c o n t ' d Percentile Case No.
28 20 24
27 5
29
26
Age
Diagnosis
4 yr. Congenital heart disease; tetralogy of Fallot 5 yr. Congenital heart disease; tetralogy of Fallot 5 yr. Congenital heart disease; tetralogy of Fallot 8 yr. Congenital heart disease; atrial septal defect 10 yr. Rheumatic heart disease; mitral insuftic. + stenosis 11 yr. Congenital heart disease; coarctation of the aorta: ventricular septal defect 18 yr. Congenital heart disease; ventricular septal defect
CHF
Wt.
Ht.
0
10
10
+t
10
3
0
10
25
0
50
25
0
25
> 25
0
25
50
0
50
50
w e i g h t a n d 18 b e l o w t h e f i f t i e t h p e r c e n t i l e f o r height. T h e r e w e r e n o s i g n i f i c a n t d i f f e r e n c e s between the two groups at the third and fiftieth p e r c e n t i l e s for h e i g h t a n d w e i g h t .
Discussion The estimation of erythrocyte glutathione r e d u c t a s e p e r m i t s , for t h e first t i m e , a specific a n d s e n s i t i v e m e a n s t o d e t e r m i n e r i b o f l a v i n deficiency. S t u d i e s w i t h e x p e r i m e n t a l r i b o f l a v i n defic i e n c y in t h e r a t TM a n d in t h e h u m a n b e i n g 11 d e m o n s t r a t e d t h a t a n i n c r e a s e in A C v a l u e s w a s a n e a r l y a n d specific i n d i c a t o r o f r i b o f l a v i n deficiency and that this increase correlated well with the duration and severity of the deficiency. In b o t h species t h e A C v a l u e s r e t u r n e d t o w i t h i n normal range after repletion with riboflavin. It was s u b s e q u e n t l y s h o w n t h a t t h i s m e t h o d is applicable to infants and children. 8 The prevalence of riboflavin deficiency as d e t e r m i n e d b y t h e b i o c h e m i c a l t e s t w a s significantly greater among the children with cardiac disease than among a group of children of the 142
Heart size (ECG, x-ray)
Second diagnosis
Right ventricular hypertrophy; normal Right ventricular hypertrophy; normal Right ventricular hypertrophy; normal
Pectus excavatum
Right ventricular hypertrophy; large Left atrial and left ventricular hypertrophy; large Left ventricular hypertrophy; normal
Drugs
Digoxin, chlorothiazide
Penicillin
Right ventricular hypertrophy; normal
Hb (Gm./ dl.)
EGRA C*
14.7
1.0
14.7
1.0
17.5
1.0
12.6
1.0
13.0
1.0
14.0
1.0
18.0
1.17
same socioeconomic level without heart disease.
Growth
and development.
There
were
no
differences in h e i g h t a n d w e i g h t b e t w e e n t h e children with heart disease with and without r i b o f l a v i n deficiency. A s a g r o u p , h o w e v e r , t h e children with cardiac disease were smaller and w e i g h e d less t h a n n o r m a l c h i l d r e n o f t h e s a m e socioeconomic status and ethnic background. O n l y e i g h t o f t h e 31 s t u d y s u b j e c t s w e r e a t t h e f i f t i e t h p e r c e n t i l e or h i g h e r for w e i g h t a n d h e i g h t . I t is a p p a r e n t t h a t t h e r e t a r d a t i o n of g r o w t h w a s not solely attributable to riboflavin deficiency. C a r d i a c d i s e a s e . T h e h e a r t l e s i o n s in b o t h t h e riboflavin-deficient and non-riboflavin-deficient groups were similar; however, there was a greater o c c u r r e n c e of c o n g e s t i v e h e a r t f a i l u r e a m o n g t h e d e f i c i e n t c h i l d r e n . T h i s m a y h a v e c o n t r i b u t e d to t h e v i t a m i n d e f i c i e n c y s i n c e t h e s e s e r i o u s l y ill children probably had a poorer dietary intake combined with gastrointestinal malabsorption w h i c h Often a c c o m p a n i e s c o n g e s t i v e h e a r t failure. There was no correlation between riboflavin August, 1976, Vol. 92, No. 2
Riboflavin deficiency in heart disease
deficiency and duration of the heart disease, the d e f i c i e n c y o c c u r r i n g in b o t h t h e y o u n g e r a n d older children. T h e r e is n o r e a s o n t o b e l i e v e t h a t t h e n u t r i t i o n a l deficiencies in c h i l d r e n w i t h c a r d i a c d i s e a s e a r e l i m i t e d t o t h a t o f folic a c i d a n d r i b o f l a v i n . The latter have been studied since specific and quantitative methods are available for these p u r p o s e s . I t is p r o b a b l e , h o w e v e r , t h a t t h e s e children may be subject to multiple nutritional deficiencies w h i c h a r e t h e r e s u l t o f p o o r a p p e t i t e , m a l a b s o r p t i o n in t h o s e w i t h c o n g e s t i v e h e a r t failure, and possibly other factors presently not known. The B vitamins are concerned with tissue respiration and deficiencies may affect not only heart tissue metabolism but the general well b e i n g o f t h e child. I t is t h e r e f o r e i m p o r t a n t t o insure that each child with cardiac disease receives an adequate intake of essential nutrients a n d t h a t h e be c h e c k e d p e r i o d i c a l l y f o r n u t r i t i o n a l deficiencies.
Summary Thirty-one infants and children with cardiac disease were randomly selected to determine w h e t h e r r i b o f l a v i n d e f i c i e n c y is m o r e p r e v a l e n t among those with cardiac disease than among a group of comparable socioeconomic status witho u t c a r d i a c disease. R i b o f l a v i n s t u d i e s w e r e i n i t i a t e d s i n c e i t is a r e p r e s e n t a t i v e m e m b e r o f t h e B c o m p l e x a n d a specific a n d s e n s i t i v e b i o c h e m i c a l m e t h o d is a v a i l a b l e t o d e t e c t d e f i c i e n c y o f this vitamin. The method involves the determination of the degree of saturation of erythrocyte glutathione reductase. Twenty-seven of the subjects had congenital heart disease and four h a d r h e u m a t i c h e a r t d i s e a s e . E l e v e n o f t h e 31 h a d
American Heart Journal
evidence of riboflavin deficiency, a significantly higher prevalence than among the group without c a r d i a c disease. T h e d e f i c i e n c y e x i s t e d a m o n g those with congenital and acquired cardiac disease. T h e r e w a s a g r e a t e r t e n d e n c y for t h e vitamin deficiency to occur among those with congestive heart failure. These studies indicate that nutritional deficiencies may be more prevalent among infants and children with cardiac disease than was previously thought.
REFERENCES 1. Gr~isbeck,R., Bjorksten, F., and Nyberg, W.: Forminoglutaminsyra i urin vid folsyrabrist, Nord. Med. 6 6:1343, 1961. 2. Daly, J. J., and Rose, D. P.: Excretion of urocanic acid following oral histidine in heart failure, Br. Heart J. 28:698, 1966. 3. Brody, J. I., Soltys, H. D., and Zinsser, H. F.: Folic acid deficiency in congestive heart failure, B r . Heart J. 31:741, 1969. 4. Rook, G. D., Lopez, R., Shimizu, N., and Cooperman, J. M.: Folic acid deficiency in infants and children with heart disease, Br. Heart J. 35:87, 1973. 5. Hyde, R. D,, and Loehry, C. A . E. H.: Folic acid malabsorption in cardiac failure, Gut 9:717, 1968. 6. Reteif, F. P., and Huskisson, J. J.: Serum and urinary folate in liver disease, Br. Med. J. 2:150, 1969. 7. Glatzle, D., KOrner, W. F., Christeller, S., amd Wiss, 0.: Method for the detection of a biochemical riboflavin deficiency, Int. J. Vitamin Res. 40:166, 1970. 8. Cooperman, J. M., Cole, H. S., Gordon, M., and Lopez, R.: Erythrocyte glutathione reductase as a measure of riboflavin nutritional status of pregnant women and newborns, Proc. Soc. Exp. Biol. Med. 143:326, 1973. 9. Cole, H. S., Lopez, R., and Cooperman, J. M.: Quantitative estimation of riboflavin deficiency in a low socioeconomic pediatric population by a new method, Pediatr. Res. 8:379, 1974. 10. Tillotson, J. A., and Sauberlich, H. E.: Effect of riboflavin depletion and repletion on the erythrocyte glutathione reductase in the rat, J. Nutr. 101:1459, i971. 11. Tillotson, J. A., and Baker, E. M.: An enzymatic measurement of the riboflavin status in man, Am. J. Clin. Nutr. 25:425, 1972.
143
It has been shown t h a t folic acid deficiency m a y be a complication of h e a r t disease in adults ~-:~and in infants and children2 Among the m e c h a n i s m s advanced to explain this deficiency were gastrointestinal malabsorption 5 and excessive u r i n a r y excretion. ~ However, these mechanisms m a y also result in other vitamin deficiencies. I n order to determine whether the l a t t e r do occur, we investigated in infants and children with congenital and acquired h e a r t disease, a deficiency of riboflavin, a m e m b e r of the B complex of vitamins.
Subjects and methods T h i r t y one children ranging in age from 1 m o n t h to 18 years were the s t u d y subjects. Twenty-seven had congenital cardiac defects and f o u r had rheumatic h e a r t disease. C o n v e n t i o n a l x-rays and 13 lead electrocardiograms were done on all patients. T h e 27 with congenital h e a r t disease u n d e r w e n t cardiac c a t h e t e r i z a t i o n and angiography. E r y t h r o c y t e s e d i m e n t a t i o n rate, Creactive protein, antistreptolysin O titer, serum complement, e n z y m e studies, stool analyses, and various cultures were done where necessary to make the diagnosis. T h e lesion in each case is described in Tables I and II. T h e heights and weights of each child were recorded and plotted on the percentile c h a r t developed by Dr. H a r o l d C. S t u a r t for comparison of these children with the general population. 4 Riboflavin deficiency was d e t e r m i n e d from the From the Department of Pediatrics, New York Medical College, Flower and Fifth Avenue Hospitals, and Metropolitan Hospital Center, New York, N. Y. Received for publication May 27, 1975. Reprint requests: Dr. Jack M. Cooperman, Department of Pediatrics, New York Medical College, 1249 Fifth Ave., New York, N. Y. 10029.
August, 1976, Vol. 92, No. 2, pp. 139-143
estimation of the degree of s a t u r a t i o n of e r y t h r o cyte glutathione reductase ( E G R ) with flavin adenine dinucleotide (FAD), by a modification of the m e t h o d of Glatzle and associates. 7 Details of this m e t h o d were previously reported. 8 T h e results are expressed as the activity coefficient (AC) which is a measure of the i n c r e m e n t of E G R activity when exogenous F A D is added to the reaction mixture. N o r m a l values range from 0.9 to 1.2. Values above 1.2 indicate deficiency i n infants and children. The prevalence of riboflavin deficiency in the children with h e a r t disease was c o m p a r e d to t h a t in a group of 100 n o r m a l infants and children of the same socioeconomic level who were free of acute or chronic infection, diarrhea, or vomiting.
Results Eleven of the 31 children with cardiac disease had biochemical evidence of riboflavin deficiency with AC values ranging from 1.29 to 1.71 (Table I). This was a significantly higher prevalence t h a n t h a t in a group of normal children of the same socioeconomic status (p < 0.005). In the l a t t e r group 11 of 100 had biochemical evidence of riboflavin deficiency. In each case, the elevated AC values could be returned to within n o r m a l limits in 5 to 8 days, when the riboflavin-deficient children were given 2.4 mg of riboflavin per day orally. Cardiac disease in study subjects. Eight of the 11 children with evidence of riboflavin deficiency had congenital h e a r t disease, four with ventricular septal defect, one with ventricular septal defect with aortic insufficiency, two with tetralogy of Fallot, and one with tricuspid atresia. T h r e e had r h e u m a t i c heart disease with mitral
American Heart Journal
139
Steier, Lopez, and Cooperman
Table I. R i b o f l a v i n - d e f i c i e n t
patients
Percentile Case No.
Age (yr.)
15
1/2
6
1
12
1
19
21~
2
3
4
3
8
5
31
10
25
12
1
13
7
13
Wt.
Ht.
Heart size (ECG, x-ray)
Second diagnosis
EGRA C*
Diagnosis
CHF
Congenital heart disease; ventricnlar septal defect Congenital heart disease; ventricular septal defect Congenital heart disease; tricuspid atresia Congenital heart disease; tetralogy of Fallot Congenital heart disease; tetralogy of Fallot Congenital heart disease; yentricular septal defect Congenital heart disease; yentricular septal defect Rheumatic heart disease; mitral insuffic. + myocarditis Congenital heart disease; ventricular septal defect; aortic insuffic. Rheumatic heart disease; m i t r a l insuffic. + myocarditis Rheumatic heart disease; mitral insuffic. + myocarditis
+
10
25
Left ventricular Pneumonia hypertrophy; large
Penicillin, digoxin, chlorothiazide
11.3
1.6
+
> 10
25
Left ventricular Pneumonia hypertrophy; large
Penicillin, digoxin
10.8
1.5
0
3
3
-
17.8
1.71
0
10
25
-
16.8
1.3
0
> 3
> 10
-
17.3
1.5
+
> 3
3
Left ventricular hypertrophy; normal Right ventricular hypertrophy; normal Right ventricular hypertrophy; normal Biventricular Pneumonia hypertrophy; large
Penicillin, digoxin
11.5
1.57
+
> 50
> 25
Penicillin, digoxin, chlorothiazide
9.8
1.43
+
75
50
Left ventricular hypertrophy; large
-
-
14.2
1.5
0
25
50
Normal; normal
-
-
12.5
1.3
+
> 50
> 25
Left ventricular hypertrophy; large
-
Penicillin, prednisone, digoxin
13.0
1.29
+
50
75
Left ventricular hypertrophy; large
Penicillin, prednisone, digoxin, KC1
12.0
1.38
Biventricular hypertrophy; large
Pneumonia
Asthma
Drugs
Hb (Gm./ dl.)
*EGRAC: erythrocyte glutathione reductase activity coefficient.
insufficiency and myocarditis. S e v e n o f t h e 11 were in congestive heart failure (CHF) when these studies were performed. O f t h e 20 w i t h n o e v i d e n c e o f r i b o f l a v i n d e f t c i e n c y , 19 h a d c o n g e n i t a l d i s e a s e a n d o n e h a d rheumatic heart disease. Only four were in congestive heart failure (Table II).
Socioeconomic factors. A l l the infants and 140
children in this study were from the same socioeconomic level and no gross dietary differences could be discerned between the groups. S e v e n o f t h e 11 r i b o f l a v i n - d e f i c i e n t p a t i e n t s were below the fiftieth percentile for weight and eight were below the fiftieth percentile for height. I n c o m p a r i s o n , 10 o f t h e 20 w i t h o u t r i b o f l a v i n deficiency were below the fiftieth percentile for
August, 1976, Vol. 92, No. 2
Riboflavin deficiency in heart disease
Table II. Non-riboflavin-deficient patients Percentile Case No. 21
22
16
3
14
17
23
10
30
18
13
11
9
Age
Diagnosis
1 mo. Congenital heart disease; transposition of great vessels 2 mo. Congenital heart disease; tricuspid atresia 2 too. Congenital heart disease; tricuspid atresia 1 yr. Congenital heart disease; tricuspid atresia 1 yr. Congenital heart disease; tetralogy of Fallot 1 yr. Congenital heart disease, ventricular septal defect; persistent ductus arteriosus 1 yr. Congenital heart disease; ventricular septal defect 2 yr. Congenital heart disease; ventricular septal defect; atrial septal defect 2 yr. Congenital heart disease; patent ductus arteriosus 21/2 yr: Congenital heart disease; tetralogy of Fallot 2V2 yr. Congenital heart disease; ventricular septal defect; aortic insuffic. 21/2 yr. Congenital heart disease; ventricular septal defect; atrial septal defect; pulmonary valvular stenosis 3 yr. Congenital heart disease; tetralogy of Fallot
Ht.
Heart size (ECG, x-ray)
Second diagnosis
Hb (Gm./
EG-
Drugs
dl.)
RA C*
Digoxin, penicillin
14.8
1.0
15.3
1.0
16.4
1.0
16.5
1.0
15.4
1.0
12.4
1.0
12.0
1.0
CHF
Wt.
0
< 10
90
Right ventricular hypertrophy; large
0
25
25
0
3
10
0
> 10
> 25
0
3
10
+
50
25
Left ventricular hypertrophy; normal Left ventricular hypertrophy; normal Left ventricular hypertrophy; normal Left ventricular hypertrophy; normal Left ventricular hypertrophy; large
+
3
10
Biventricular hypertrophy; large
+
10
25
Right ventricular hypertrophy; normal
12.2
0.9
0
50
25
Upper limits of normal: normal
13.6
1.0
0
3
25
17.4
1.0
0
10
25
Right ventricular hypertrophy; normal Left ventricular hypertrophy; normal
12.4
1.0
0
3
25
Right ventricular hypertrophy; normal
14.0
0.9
0
25
25
Right ventricular hypertrophy; normal
17.2
1.0
-
-
Digoxin
*EGRAC: erythrocyte glutathione reductase activity coefficient. tPostoperative.
American Heart J o u r n a l
141
Steier, Lopez, and Cooperman
Table II. c o n t ' d Percentile Case No.
28 20 24
27 5
29
26
Age
Diagnosis
4 yr. Congenital heart disease; tetralogy of Fallot 5 yr. Congenital heart disease; tetralogy of Fallot 5 yr. Congenital heart disease; tetralogy of Fallot 8 yr. Congenital heart disease; atrial septal defect 10 yr. Rheumatic heart disease; mitral insuftic. + stenosis 11 yr. Congenital heart disease; coarctation of the aorta: ventricular septal defect 18 yr. Congenital heart disease; ventricular septal defect
CHF
Wt.
Ht.
0
10
10
+t
10
3
0
10
25
0
50
25
0
25
> 25
0
25
50
0
50
50
w e i g h t a n d 18 b e l o w t h e f i f t i e t h p e r c e n t i l e f o r height. T h e r e w e r e n o s i g n i f i c a n t d i f f e r e n c e s between the two groups at the third and fiftieth p e r c e n t i l e s for h e i g h t a n d w e i g h t .
Discussion The estimation of erythrocyte glutathione r e d u c t a s e p e r m i t s , for t h e first t i m e , a specific a n d s e n s i t i v e m e a n s t o d e t e r m i n e r i b o f l a v i n deficiency. S t u d i e s w i t h e x p e r i m e n t a l r i b o f l a v i n defic i e n c y in t h e r a t TM a n d in t h e h u m a n b e i n g 11 d e m o n s t r a t e d t h a t a n i n c r e a s e in A C v a l u e s w a s a n e a r l y a n d specific i n d i c a t o r o f r i b o f l a v i n deficiency and that this increase correlated well with the duration and severity of the deficiency. In b o t h species t h e A C v a l u e s r e t u r n e d t o w i t h i n normal range after repletion with riboflavin. It was s u b s e q u e n t l y s h o w n t h a t t h i s m e t h o d is applicable to infants and children. 8 The prevalence of riboflavin deficiency as d e t e r m i n e d b y t h e b i o c h e m i c a l t e s t w a s significantly greater among the children with cardiac disease than among a group of children of the 142
Heart size (ECG, x-ray)
Second diagnosis
Right ventricular hypertrophy; normal Right ventricular hypertrophy; normal Right ventricular hypertrophy; normal
Pectus excavatum
Right ventricular hypertrophy; large Left atrial and left ventricular hypertrophy; large Left ventricular hypertrophy; normal
Drugs
Digoxin, chlorothiazide
Penicillin
Right ventricular hypertrophy; normal
Hb (Gm./ dl.)
EGRA C*
14.7
1.0
14.7
1.0
17.5
1.0
12.6
1.0
13.0
1.0
14.0
1.0
18.0
1.17
same socioeconomic level without heart disease.
Growth
and development.
There
were
no
differences in h e i g h t a n d w e i g h t b e t w e e n t h e children with heart disease with and without r i b o f l a v i n deficiency. A s a g r o u p , h o w e v e r , t h e children with cardiac disease were smaller and w e i g h e d less t h a n n o r m a l c h i l d r e n o f t h e s a m e socioeconomic status and ethnic background. O n l y e i g h t o f t h e 31 s t u d y s u b j e c t s w e r e a t t h e f i f t i e t h p e r c e n t i l e or h i g h e r for w e i g h t a n d h e i g h t . I t is a p p a r e n t t h a t t h e r e t a r d a t i o n of g r o w t h w a s not solely attributable to riboflavin deficiency. C a r d i a c d i s e a s e . T h e h e a r t l e s i o n s in b o t h t h e riboflavin-deficient and non-riboflavin-deficient groups were similar; however, there was a greater o c c u r r e n c e of c o n g e s t i v e h e a r t f a i l u r e a m o n g t h e d e f i c i e n t c h i l d r e n . T h i s m a y h a v e c o n t r i b u t e d to t h e v i t a m i n d e f i c i e n c y s i n c e t h e s e s e r i o u s l y ill children probably had a poorer dietary intake combined with gastrointestinal malabsorption w h i c h Often a c c o m p a n i e s c o n g e s t i v e h e a r t failure. There was no correlation between riboflavin August, 1976, Vol. 92, No. 2
Riboflavin deficiency in heart disease
deficiency and duration of the heart disease, the d e f i c i e n c y o c c u r r i n g in b o t h t h e y o u n g e r a n d older children. T h e r e is n o r e a s o n t o b e l i e v e t h a t t h e n u t r i t i o n a l deficiencies in c h i l d r e n w i t h c a r d i a c d i s e a s e a r e l i m i t e d t o t h a t o f folic a c i d a n d r i b o f l a v i n . The latter have been studied since specific and quantitative methods are available for these p u r p o s e s . I t is p r o b a b l e , h o w e v e r , t h a t t h e s e children may be subject to multiple nutritional deficiencies w h i c h a r e t h e r e s u l t o f p o o r a p p e t i t e , m a l a b s o r p t i o n in t h o s e w i t h c o n g e s t i v e h e a r t failure, and possibly other factors presently not known. The B vitamins are concerned with tissue respiration and deficiencies may affect not only heart tissue metabolism but the general well b e i n g o f t h e child. I t is t h e r e f o r e i m p o r t a n t t o insure that each child with cardiac disease receives an adequate intake of essential nutrients a n d t h a t h e be c h e c k e d p e r i o d i c a l l y f o r n u t r i t i o n a l deficiencies.
Summary Thirty-one infants and children with cardiac disease were randomly selected to determine w h e t h e r r i b o f l a v i n d e f i c i e n c y is m o r e p r e v a l e n t among those with cardiac disease than among a group of comparable socioeconomic status witho u t c a r d i a c disease. R i b o f l a v i n s t u d i e s w e r e i n i t i a t e d s i n c e i t is a r e p r e s e n t a t i v e m e m b e r o f t h e B c o m p l e x a n d a specific a n d s e n s i t i v e b i o c h e m i c a l m e t h o d is a v a i l a b l e t o d e t e c t d e f i c i e n c y o f this vitamin. The method involves the determination of the degree of saturation of erythrocyte glutathione reductase. Twenty-seven of the subjects had congenital heart disease and four h a d r h e u m a t i c h e a r t d i s e a s e . E l e v e n o f t h e 31 h a d
American Heart Journal
evidence of riboflavin deficiency, a significantly higher prevalence than among the group without c a r d i a c disease. T h e d e f i c i e n c y e x i s t e d a m o n g those with congenital and acquired cardiac disease. T h e r e w a s a g r e a t e r t e n d e n c y for t h e vitamin deficiency to occur among those with congestive heart failure. These studies indicate that nutritional deficiencies may be more prevalent among infants and children with cardiac disease than was previously thought.
REFERENCES 1. Gr~isbeck,R., Bjorksten, F., and Nyberg, W.: Forminoglutaminsyra i urin vid folsyrabrist, Nord. Med. 6 6:1343, 1961. 2. Daly, J. J., and Rose, D. P.: Excretion of urocanic acid following oral histidine in heart failure, Br. Heart J. 28:698, 1966. 3. Brody, J. I., Soltys, H. D., and Zinsser, H. F.: Folic acid deficiency in congestive heart failure, B r . Heart J. 31:741, 1969. 4. Rook, G. D., Lopez, R., Shimizu, N., and Cooperman, J. M.: Folic acid deficiency in infants and children with heart disease, Br. Heart J. 35:87, 1973. 5. Hyde, R. D,, and Loehry, C. A . E. H.: Folic acid malabsorption in cardiac failure, Gut 9:717, 1968. 6. Reteif, F. P., and Huskisson, J. J.: Serum and urinary folate in liver disease, Br. Med. J. 2:150, 1969. 7. Glatzle, D., KOrner, W. F., Christeller, S., amd Wiss, 0.: Method for the detection of a biochemical riboflavin deficiency, Int. J. Vitamin Res. 40:166, 1970. 8. Cooperman, J. M., Cole, H. S., Gordon, M., and Lopez, R.: Erythrocyte glutathione reductase as a measure of riboflavin nutritional status of pregnant women and newborns, Proc. Soc. Exp. Biol. Med. 143:326, 1973. 9. Cole, H. S., Lopez, R., and Cooperman, J. M.: Quantitative estimation of riboflavin deficiency in a low socioeconomic pediatric population by a new method, Pediatr. Res. 8:379, 1974. 10. Tillotson, J. A., and Sauberlich, H. E.: Effect of riboflavin depletion and repletion on the erythrocyte glutathione reductase in the rat, J. Nutr. 101:1459, i971. 11. Tillotson, J. A., and Baker, E. M.: An enzymatic measurement of the riboflavin status in man, Am. J. Clin. Nutr. 25:425, 1972.
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